Details
Stereochemistry | ACHIRAL |
Molecular Formula | C21H20N4O3 |
Molecular Weight | 376.4085 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NC1=CC=CC=C1NC(=O)C2=CC=C(CNC(=O)OCC3=CN=CC=C3)C=C2
InChI
InChIKey=INVTYAOGFAGBOE-UHFFFAOYSA-N
InChI=1S/C21H20N4O3/c22-18-5-1-2-6-19(18)25-20(26)17-9-7-15(8-10-17)13-24-21(27)28-14-16-4-3-11-23-12-16/h1-12H,13-14,22H2,(H,24,27)(H,25,26)
Molecular Formula | C21H20N4O3 |
Molecular Weight | 376.4085 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionSources: http://adisinsight.springer.com/drugs/800012663Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/17383217
https://www.ncbi.nlm.nih.gov/pubmed/21888556
https://www.ncbi.nlm.nih.gov/pubmed/12975486
Sources: http://adisinsight.springer.com/drugs/800012663
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/17383217
https://www.ncbi.nlm.nih.gov/pubmed/21888556
https://www.ncbi.nlm.nih.gov/pubmed/12975486
Entinostat (MS-275) is an orally active, highly selective, small-molecule histone deacetylase inhibitor (HDACi) derived from benzamide. Entinostat preferentially inhibited HDAC1 versus HDAC3 and had no inhibitory activity toward HDAC8. The time to maximum plasma concentration (tmax) of entinostat ranged from 0.5 to 60h (median of 2h). Elimination of the drug was bi-exponential, with a terminal half-life of 30-80h. Entinostat is a well-tolerated that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20657706 | https://www.ncbi.nlm.nih.gov/pubmed/16432198
Curator's Comment: Entinostat (MS-275) is a potent brain region-selective HDAC inhibitor in mice.
https://www.ncbi.nlm.nih.gov/pubmed/16432198
Other study demostartes poor Entinostat (MS-275) brain penetration in non-human primates and rodents.
https://www.ncbi.nlm.nih.gov/pubmed/20657706
No human data reported to date.
Originator
Sources: http://adisinsight.springer.com/drugs/800012663
Curator's Comment: # Nihon Schering; Pfizer; University of Tokyo
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL325 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486 |
0.3 µM [IC50] | ||
Target ID: CHEMBL1829 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486 |
8.0 µM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
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Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/26133921/ |
no | |||
yes [IC50 0.73 uM] | ||||
yes [IC50 9.2 uM] | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/21245100/ |
yes | |||
yes | ||||
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
no | ||||
no | ||||
no |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells. | 2004 Apr 1 |
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Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells. | 2004 Jun 10 |
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Determination of MS-275, a novel histone deacetylase inhibitor, in human plasma by liquid chromatography-electrospray mass spectrometry. | 2004 May 25 |
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Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. | 2005 Jul |
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In vivo imaging of retinoic acid receptor beta2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells. | 2005 Jun 15 |
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Histone deacetylase inhibitors and cancer: from cell biology to the clinic. | 2005 Mar |
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Epigenetic modulation of retinoic acid receptor beta2 by the histone deacetylase inhibitor MS-275 in human renal cell carcinoma. | 2005 May 1 |
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Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases. | 2006 Aug |
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Histone deacetylase inhibitors in cancer therapy. | 2006 Aug-Sep |
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Curcumin is an inhibitor of p300 histone acetylatransferase. | 2006 Mar |
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Anticancer activity of MS-275, a novel histone deacetylase inhibitor, against human endometrial cancer cells. | 2006 Mar-Apr |
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Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275. | 2006 May |
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HDAC inhibitors induce apoptosis in glucocorticoid-resistant acute lymphatic leukemia cells despite a switch from the extrinsic to the intrinsic death pathway. | 2007 |
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Relationship between embryonic histonic hyperacetylation and axial skeletal defects in mouse exposed to the three HDAC inhibitors apicidin, MS-275, and sodium butyrate. | 2007 Aug |
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Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models. | 2007 Aug 1 |
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Measuring cytotoxicity: a new perspective on LC50. | 2007 Jan-Feb |
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Histone deacetylase inhibitors affect dendritic cell differentiation and immunogenicity. | 2007 Jul 1 |
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Histone deacetylase inhibitors induce cell death and enhance the apoptosis-inducing activity of TRAIL in Ewing's sarcoma cells. | 2007 Nov |
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Antiproliferative activities of a library of hybrids between indanones and HDAC inhibitor SAHA and MS-275 analogues. | 2007 Nov 15 |
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Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. | 2007 Sep 7 |
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Identification of ligand features essential for HDACs inhibitors by pharmacophore modeling. | 2008 Apr |
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MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours. | 2008 Apr 8 |
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Sp1-mediated TRAIL induction in chemosensitization. | 2008 Aug 15 |
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Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. | 2008 Dec 15 |
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Regulation of arginase-1 expression in macrophages by a protein kinase A type I and histone deacetylase dependent pathway. | 2008 Feb 1 |
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Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21waf1 promoter in acute myelogenous leukemia cell. | 2008 Jul |
|
p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage. | 2008 Jun 5 |
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Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases. | 2008 Mar 15 |
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Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts. | 2008 Mar 15 |
|
MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. | 2008 Sep |
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Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors. | 2009 |
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[Effects of histone deacetylase inhibitor MS-275 on expression of survivin and NF-kappaB in the human myeloma cell line U266 cells]. | 2009 Apr |
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Reactivation of death receptor 4 (DR4) expression sensitizes medulloblastoma cell lines to TRAIL. | 2009 Jul |
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Epigenetic modifiers: basic understanding and clinical development. | 2009 Jun 15 |
|
"Shock and kill" effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence. | 2009 Jun 2 |
|
Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes. | 2009 May |
|
Three epigenetic drugs up-regulate homeobox gene Rhox5 in cancer cells through overlapping and distinct molecular mechanisms. | 2009 Nov |
|
HDAC inhibitor SNDX-275 induces apoptosis in erbB2-overexpressing breast cancer cells via down-regulation of erbB3 expression. | 2009 Nov 1 |
|
Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, in human colon cancer models. | 2009 Oct |
|
Epigenetic influences on sensory regeneration: histone deacetylases regulate supporting cell proliferation in the avian utricle. | 2009 Sep |
|
Antidepressant actions of histone deacetylase inhibitors. | 2009 Sep 16 |
|
Anti-leukemia activity of MS-275 histone deacetylase inhibitor implicates 4-1BBL/4-1BB immunomodulatory functions. | 2009 Sep 17 |
|
HDAC inhibitors, MS275 and SBHA, enhances cytotoxicity induced by oxaliplatin in the colorectal cancer cell lines. | 2009 Sep 18 |
|
Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. | 2009 Sep 24 |
|
MS275 enhances cytotoxicity induced by 5-fluorouracil in the colorectal cancer cells. | 2010 Feb 10 |
|
Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation. | 2010 Jan 7 |
Patents
Sample Use Guides
Phase I trial data have shown that daily dosing of entinostat is not tolerated. Administration of the drug every 2 weeks or weekly at doses of ≤10 mg/m2 was much better tolerated than daily dosing. The recommended phase II dose for entinostat is 4 mg/ m2 once weekly (solid tumors).
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12839953
Entinostat (MS-275) exerts dose-dependent effects in human leukemia cells, i.e., p21(CIP1/WAF1)-dependent growth arrest and differentiation at low drug concentrations (e.g., 1 uM) and a marked induction of ROS, mitochondrial damage, caspase activation, and apoptosis at higher concentrations (e.g., 5 uM).
Substance Class |
Chemical
Created
by
admin
on
Edited
Wed Jul 05 23:27:03 UTC 2023
by
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on
Wed Jul 05 23:27:03 UTC 2023
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Record UNII |
1ZNY4FKK9H
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Record Status |
Validated (UNII)
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Record Version |
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EU-Orphan Drug |
EU/3/10/732
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NCI_THESAURUS |
C1946
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209783-80-2
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4261
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DB11841
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ENTINOSTAT
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100000126009
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DTXSID0041068
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C1863
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442532-99-2
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9016
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TT-136
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SUB33300
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706995
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CHEMBL27759
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1ZNY4FKK9H
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Related Record | Type | Details | ||
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TARGET->WEAK INHIBITOR |
Enzymatic Inhibition
IC50
|
||
|
TARGET->WEAK INHIBITOR |
Strongly inhibits HDAC3 in cell-free assays. Phase 3.
INHIBITOR
IC50
|
||
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TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
|
||
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TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
|
||
|
TARGET -> INHIBITOR |
Strongly inhibits HDAC1 in cell-free assays. Phase 3.
INHIBITOR
IC50
|
||
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TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
|
||
|
TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
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TARGET -> INHIBITOR |
Enzymatic Inhibition
IC50
|
Related Record | Type | Details | ||
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ACTIVE MOIETY |
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